Summary, discussion and future perspectives 147 CHAPTER 8 was discovered, but no higher clear resection margin rate.13 In a recent comparison of overall curable LRRC of the CHE and Karolinska Institute, no impact of reirradiation on clear resection margin rate and overall survival could be demonstrated. Therefore, the debate certainly cannot be closed in favour of reirradiation. Despite favourable findings, no convincing evidence is available for either approach. The high local re-recurrence rate may indicate that the effective dose is too low in possibly radioresistant cell clones. A logical approach could be to try to enhance tumour response. In total neoadjuvant treatment protocols for locally advanced primary rectal cancer adding systemic treatment either as induction or consolidation therapy was successful in obtaining better tumour response. In this thesis this principle has been adopted for LRRC. As shown in chapter 2, dose intensification innon-radiotherapy naive LRRC led to a significant higher pathological complete response rate from 8.5 percent before introducing induction chemotherapy (ICT) to 19 percent after introduction of ICT, which also resulted in an improved overall survival.14 In chapter 4, for a specific subsite of LRRC an even higher tumour response was noted. In lateral recurrences ICT led to a pCR rate of 31 percent versus 8 percent without ICT. These promising results are basedon small numbers, butmay indicate that the aetiology of a local recurrence influences response to treatment. Lateral local recurrences are associated with persisting lateral lymph nodes after chemoradiation for primary rectal cancer.15 Response In chapter 3 tumour response after ICT seems to be an independent prognostic variable apart from clear resectionmargins. Tumour response after ICT also was a significantly strong indicator for metastasis free survival, which is the principle cause of death after developing LRRC.16 Further research is needed to define the exact role of adding systemic treatment to the preoperative treatment of LRRC patients. It could be imaginable that the local response to ICT is mediated by a radiosensitizing effect leading to a higher biological dose in reirradiation patients, but an equally reasonable explanation would be the effect on micrometastases and subsequent reduction of development of metastases. The aetiology of LRRC may become more important at MDT discussion in order to decide for which patients ICT may be beneficial. Patients who have had synchronic or metachronic curable metastases during the treatment of their primary tumour have a much better prognosis than patients who present with synchronic metastasis at their treatment for LRRC.17
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